title: Association between polymorphisms of endothelial nitric oxide synthase gene (NOS3) and left posterior wall thickness (LPWT) of the heart in Fabry disease.
abstract: Fabry disease is an X-chromosomal storage disorder due to loss-of-function mutations of the GLA gene encoding the lysosomal enzyme α-galactosidase A. Accumulating glycosphingolipid deposits disturb the function of various cells, in particular that of myocytes, arterial smooth-muscle cells, and vascular endothelium. Hypertrophic cardiomyopathy, for example measured by left posterior wall thickness (LPWT) of the heart, represents a major component of Fabry disease morbidity in adult patients. Endothelium-derived nitric oxide (eNO), produced by eNO synthase (eNOS), is a key regulator of vessel wall function and cardiovascular homeostasis. We analysed the effect of the polymorphisms c.894G > T (p.Glu298Asp) in exon 7 and the 27 bp tandem repeat (VNTR; allele a: 4 and allele b: 5 repeats) in intron 4 of the NOS3 gene, encoding eNOS, on LPWT of 102 patients with Fabry disease. For the association analysis, the distance of each patient's LPWT value from the cohort-specific, age-dependent regression line point (expected values) was used. In the cohort of 46 male patients, LPWT mean value of the group with GG genotype at position c.894 was smaller by 1 mm than that of (GT + TT) (p = 0.058). LPWT of patients with bb was thicker by 1.4 mm than that of (ab + aa) (p = 0.022). In patients with haplotype Ga, a thinner LPWT was seen than in those with Tb (p = 0.006). While no correlation was found between the GLA genotype and LPWT, the difference of 2.44 mm between the relative LPWT mean values of the two extreme NOS3 groups corresponds to the absolute LPWT increase that an average male patient with Fabry disease experiences during about 12 years. These are the first data showing a significant association of non-GLA-derived sequence variants with the cardiac phenotype in Fabry disease that may in part explain the great phenotypic variability of the disease.
authors.affiliation: Institute of Human Genetics, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Rohard
authors.forename: E
authors.initials: E
authors.lastname: Schaefer
authors.forename: C
authors.initials: C
authors.lastname: Kampmann
authors.forename: M
authors.initials: M
authors.lastname: Beck
authors.forename: A
authors.initials: A
authors.lastname: Gal
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002312:Cardiomyopathy, Hypertrophic / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D005091:Exons; D000795:Fabry Disease / Q000150:complications / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005858:Germany; D006239:Haplotypes; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics*; D007438:Introns; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats; D020125:Mutation, Missense; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D012044:Regression Analysis; D012737:Sex Factors; D014463:Ultrasonography; D055815:Young Adult; D000519:alpha-Galactosidase / Q000235:genetics
chemical_list: C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D000519:alpha-Galactosidase